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Epigenetic-based therapies for Friedreich ataxia.

Sandi C, Sandi M, Anjomani Virmouni S, Al-Mahdawi S, Pook MA - Front Genet (2014)

Bottom Line: Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression.Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy.Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London Uxbridge, UK.

ABSTRACT
Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene silencing. Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy. Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option. In this review we summarize our current understanding of the epigenetic basis of FXN gene silencing and we discuss current epigenetic-based FRDA therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Potential epigenetic-based therapies for FRDA. Large GAA•TTC repeats in FRDA patients are associated with heterochromatin mediated FXN gene silencing. The use of specific HDAC inhibitors, HDM activators, HAT activators, HMTase inhibitors, or agRNA activation may reverse the heterochromatin to a more open chromatin structure, and may thus lead to active FXN gene transcription. This image was adapted from Festenstein (2006); Chan et al. (2013).
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Figure 3: Potential epigenetic-based therapies for FRDA. Large GAA•TTC repeats in FRDA patients are associated with heterochromatin mediated FXN gene silencing. The use of specific HDAC inhibitors, HDM activators, HAT activators, HMTase inhibitors, or agRNA activation may reverse the heterochromatin to a more open chromatin structure, and may thus lead to active FXN gene transcription. This image was adapted from Festenstein (2006); Chan et al. (2013).

Mentions: HDAC inhibitors can affect transcription by increasing acetylation of histones, transcription factors, and other proteins that regulate transcription (Butler and Bates, 2006). In view of the recent identification of histone acetylation changes at the FXN gene in FRDA, it has been proposed that the reversal of such histone modifications could represent a useful therapeutic approach for FRDA (Figure 3) (Festenstein, 2006; Herman et al., 2006). An initial study to screen for frataxin-increasing compounds by Sarsero and colleagues first demonstrated a small effect of the general HDAC inhibitor sodium butyrate on FXN gene activity using an EGFP reporter cell line (Sarsero et al., 2003). Subsequently, Gottesfeld and colleagues treated FRDA lymphoblastoid cells using a selection of commercially available HDAC inhibitors. They revealed that only the benzamide compound BML-210 produced a significant increase of FXN mRNA expression (Herman et al., 2006), although other HDAC inhibitors showed a more pronounced increase of histone acetylation without any increase in FXN expression, indicating a degree of compound specificity for FXN gene silencing (Table 2). An analog of BML-210, designated 4b, was then synthesized and was shown to directly modulate the histones associated with the FXN gene to increase FXN mRNA expression in FRDA primary lymphocytes (Herman et al., 2006). Compound 4b has subsequently been used to demonstrate amelioration of the HD phenotype in R6/2 mice without any discernible toxicity (Thomas et al., 2008). Further development of HDAC inhibitors by the Gottesfeld lab and the Repligen Corporation (Waltham, Massachusetts) identified three 2-aminobenzamide compounds, designated 106, 136, and 109, which can each significantly increase FXN mRNA and frataxin protein levels in FRDA cells with only a small effect on unaffected control cells (reviewed in Soragni et al., 2012). The exact mechanism of action of the 2-aminobenzamide HDAC inhibitors in FRDA is not known. However, compound 106 has been shown to act as selective slow-on, slow-off, tight-binding inhibitor of class I HDACs, with a preference for inhibition of HDAC3 (Chou et al., 2008; Xu et al., 2009). Compounds 106, 136, and 109 have undergone investigations to determine safety, efficacy and pharmacokinetic profile in short-term treatments of FRDA patient derived cells and KIKI knock-in mice (Chou et al., 2008; Rai et al., 2008, 2010; Soragni et al., 2008; Xu et al., 2009), and a long-term treatment in YG8R YAC transgenic mice (Sandi et al., 2011) (Table 2). Compound 109, which emerged as the most promising compound for FRDA treatment, has now been assessed in a phase I clinical trial as RG2833 (Soragni et al., 2012) and further related compounds are now under development.


Epigenetic-based therapies for Friedreich ataxia.

Sandi C, Sandi M, Anjomani Virmouni S, Al-Mahdawi S, Pook MA - Front Genet (2014)

Potential epigenetic-based therapies for FRDA. Large GAA•TTC repeats in FRDA patients are associated with heterochromatin mediated FXN gene silencing. The use of specific HDAC inhibitors, HDM activators, HAT activators, HMTase inhibitors, or agRNA activation may reverse the heterochromatin to a more open chromatin structure, and may thus lead to active FXN gene transcription. This image was adapted from Festenstein (2006); Chan et al. (2013).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042889&req=5

Figure 3: Potential epigenetic-based therapies for FRDA. Large GAA•TTC repeats in FRDA patients are associated with heterochromatin mediated FXN gene silencing. The use of specific HDAC inhibitors, HDM activators, HAT activators, HMTase inhibitors, or agRNA activation may reverse the heterochromatin to a more open chromatin structure, and may thus lead to active FXN gene transcription. This image was adapted from Festenstein (2006); Chan et al. (2013).
Mentions: HDAC inhibitors can affect transcription by increasing acetylation of histones, transcription factors, and other proteins that regulate transcription (Butler and Bates, 2006). In view of the recent identification of histone acetylation changes at the FXN gene in FRDA, it has been proposed that the reversal of such histone modifications could represent a useful therapeutic approach for FRDA (Figure 3) (Festenstein, 2006; Herman et al., 2006). An initial study to screen for frataxin-increasing compounds by Sarsero and colleagues first demonstrated a small effect of the general HDAC inhibitor sodium butyrate on FXN gene activity using an EGFP reporter cell line (Sarsero et al., 2003). Subsequently, Gottesfeld and colleagues treated FRDA lymphoblastoid cells using a selection of commercially available HDAC inhibitors. They revealed that only the benzamide compound BML-210 produced a significant increase of FXN mRNA expression (Herman et al., 2006), although other HDAC inhibitors showed a more pronounced increase of histone acetylation without any increase in FXN expression, indicating a degree of compound specificity for FXN gene silencing (Table 2). An analog of BML-210, designated 4b, was then synthesized and was shown to directly modulate the histones associated with the FXN gene to increase FXN mRNA expression in FRDA primary lymphocytes (Herman et al., 2006). Compound 4b has subsequently been used to demonstrate amelioration of the HD phenotype in R6/2 mice without any discernible toxicity (Thomas et al., 2008). Further development of HDAC inhibitors by the Gottesfeld lab and the Repligen Corporation (Waltham, Massachusetts) identified three 2-aminobenzamide compounds, designated 106, 136, and 109, which can each significantly increase FXN mRNA and frataxin protein levels in FRDA cells with only a small effect on unaffected control cells (reviewed in Soragni et al., 2012). The exact mechanism of action of the 2-aminobenzamide HDAC inhibitors in FRDA is not known. However, compound 106 has been shown to act as selective slow-on, slow-off, tight-binding inhibitor of class I HDACs, with a preference for inhibition of HDAC3 (Chou et al., 2008; Xu et al., 2009). Compounds 106, 136, and 109 have undergone investigations to determine safety, efficacy and pharmacokinetic profile in short-term treatments of FRDA patient derived cells and KIKI knock-in mice (Chou et al., 2008; Rai et al., 2008, 2010; Soragni et al., 2008; Xu et al., 2009), and a long-term treatment in YG8R YAC transgenic mice (Sandi et al., 2011) (Table 2). Compound 109, which emerged as the most promising compound for FRDA treatment, has now been assessed in a phase I clinical trial as RG2833 (Soragni et al., 2012) and further related compounds are now under development.

Bottom Line: Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression.Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy.Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosciences, School of Health Sciences and Social Care, Brunel University London Uxbridge, UK.

ABSTRACT
Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene silencing. Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy. Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option. In this review we summarize our current understanding of the epigenetic basis of FXN gene silencing and we discuss current epigenetic-based FRDA therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus